title: Long term metabolic syndrome induced by a high fat high fructose diet leads to minimal renal injury in C57BL/6 mice.
abstract: Metabolic syndrome can induce chronic kidney disease in humans. Genetically engineered mice on a C57BL/6 background are highly used for mechanistic studies. Although it has been shown that metabolic syndrome induces cardiovascular lesions in C57BL/6 mice, in depth renal phenotyping has never been performed. Therefore in this study we characterized renal function and injury in C57BL/6 mice with long-term metabolic syndrome induced by a high fat and fructose diet (HFFD). C57BL/6 mice received an 8 months HFFD diet enriched with fat (45% energy from fat) and drinking water enriched with fructose (30%). Body weight, food/water consumption, energy intake, fat/lean mass ratio, plasma glucose, HDL, LDL, triglycerides and cholesterol levels were monitored. At 3, 6 and 8 months, renal function was determined by inulin clearance and measure of albuminuria. At sacrifice, kidneys and liver were collected. Metabolic syndrome in C57BL/6 mice fed a HFFD was observed as early 4 weeks with development of type 2 diabetes at 8 weeks after initiation of diet. However, detailed analysis of kidney structure and function showed only minimal renal injury after 8 months of HFFD. HFFD induced moderate glomerular hyperfiltration (436,4 µL/min vs 289,8 µL/min; p-value=0.0418) together with a 2-fold increase in albuminuria only after 8 months of HFFD. This was accompanied by a 2-fold increase in renal inflammation (p-value=0.0217) but without renal fibrosis or mesangial matrix expansion. In addition, electron microscopy did not show alterations in glomeruli such as basal membrane thickening and foot process effacement. Finally, comparison of the urinary peptidome of these mice with the urinary peptidome from humans with diabetic nephropathy also suggested absence of diabetic nephropathy in this model. This study provides evidence that the HFFD C57BL/6 model is not the optimal model to study the effects of metabolic syndrome on the development of diabetic kidney disease.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France ; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Dissard
authors.forename: Julie
authors.initials: J
authors.lastname: Klein
authors.forename: Cécile
authors.initials: C
authors.lastname: Caubet
authors.forename: Benjamin
authors.initials: B
authors.lastname: Breuil
authors.forename: Justyna
authors.initials: J
authors.lastname: Siwy
authors.forename: Janosch
authors.initials: J
authors.lastname: Hoffman
authors.forename: Laurent
authors.initials: L
authors.lastname: Sicard
authors.forename: Laure
authors.initials: L
authors.lastname: Ducassé
authors.forename: Simon
authors.initials: S
authors.lastname: Rascalou
authors.forename: Bruno
authors.initials: B
authors.lastname: Payre
authors.forename: Marie
authors.initials: M
authors.lastname: Buléon
authors.forename: William
authors.initials: W
authors.lastname: Mullen
authors.forename: Harald
authors.initials: H
authors.lastname: Mischak
authors.forename: Ivan
authors.initials: I
authors.lastname: Tack
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Bascands
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Buffin-Meyer
authors.forename: Joost P
authors.initials: JP
authors.lastname: Schanstra
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000473:pathology / Q000652:urine*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000473:pathology / Q000652:urine*; D059305:Diet, High-Fat; D002149:Energy Intake; D005632:Fructose / Q000009:adverse effects*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000139:chemically induced / Q000473:pathology / Q000652:urine*; D051379:Mice; D008810:Mice, Inbred C57BL; D020543:Proteome / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D020543:Proteome; D014280:Triglycerides; D005632:Fructose